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Gene Section
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RLN2 (relaxin 2)
Jordan M Willcox, Alastair JS Summerlee
Department of Biomedical Sciences, Ontario Veterinary College, University of Guelph, Guelph, Ontario,
N1G 2W1, Canada (JMW, AJSS)
Published in Atlas Database: November 2009
Online updated version : http://AtlasGeneticsOncology.org/Genes/RLN2ID44421ch9p24.html
DOI: 10.4267/2042/44844
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence.
© 2010 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Identity
DNA/RNA
Other
names:
H2;
RLXH2;
bA12D24.1.1;
bA12D24.1.2; prorelaxin H2
HGNC (Hugo): RLN2
Location: 9p24.1
Local order: RLN2 is located on chromosome 9 on the
reverse strand.
Description
RLN2 is a functioning gene of 4,712 bp comprising 2
exons and 1 intron.
Transcription
The length of the transcript is 588 bp. mRNA is
expressed in high levels in ovary and placenta, and in
lower levels in fibroblasts, a number of tumours, heart
and brain.
Alternate splicing: 2 isoforms: P04090-1, P04090-2.
Pseudogene
None but there are a number of similar genes of the
same family. These include: RLN1 and RLN2 genes in
a tight cluster with INSL4 and INSL6 genes on
chromosome 9 at 9p24. The RLN3 gene is located on
chromosome 19 at 19p13.3 in close proximity to
INSL3 at 19p13.2 and the INSL5 gene is located on
chromosome 1 at 1p31.1
RLN2 is located on chromosome 9 (position shown by yellow
arrow).
Note: See also, in the Deep Insight section: RLN2 and
its role in cancer.
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(9)
841
RLN2 (relaxin 2)
Willcox JM, Summerlee AJS
Schematic representation of the transcription of the human RLN2 gene. Adapted from Bathgate et al., 2006 (with permission). The gene
is located with the RLN1, INSL4 and INSL6 genes on chromosome 9 at 9p24. The RLN2 gene consists of two exons and is transcribed to
give preprorelaxin-2 mRNA. Exon I encodes for the signal peptide, the B Chain and part of the C Chain, and Exon II encodes for the
remainder of the C Chain and the A chain of H2 relaxin. The arrows on the diagrams indicate the orientation of the genes. Although
insulin and H2 relaxin are similar, there is no report that the insulin gene possesses an intron.
(RXPF1). These receptors have a large and very
distinctive ectodomain which includes an LDLa
module at the far end of the N-terminus followed by a
LRR domain (10 LRR). It is thought that this links with
a unique hinge-like region leading into the
transmembrane domain. There are seven
Protein
transmembrane helices and an intracellular C-terminus.
Expression
mRNA and protein found in brain, heart, skin, lungs,
liver, kidney, ovary, uterus, testis, prostate and in
prostatic and mammary neoplasia. Expression induced
by a variety of factors in different tissues.
Localisation
Modified from Westhuizen et al. 2008.
Characteristic two-peptide chain hormone held together by
disulphide bonds (shown in yellow) which provide the tertiary
form of the molecule. There is a relaxin receptor binding motif
(shown in red and green).
Cytoplasm.
Function
Brain
- Increased food intake
- Mediates stress behaviour
- Increased fluid intake
- Release of a number of hypothalamic peptides
including vasopressin, oxytoxcin, LH, and angiotensin
II
Heart
- Increased rate of atrial contraction
- Increased force of atrial contraction
- Reduced fibrosis
- Differentiation and development
Description
Protein length of the precursor peptide is 185 amino
acids with a molecular weight 21,043 Daltons.
The functional peptide has 21 amino acids in the A
chain and 27 in the B chain and with a molecular
weight 5,989 Daltons.
There is a specific binding motif (see diagram above)
Arg-X-X-X-Arg-X-X-Ile/Val which are vital for
binding and the projection from the tertiary structure is
important in binding to the Type C LGR receptor
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(9)
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RLN2 (relaxin 2)
Willcox JM, Summerlee AJS
- Release of ANP
Vasculature
- Decreased blood pressure
- Decreased total peripheral resistance
- Vasodilation
Skin
- Reduced fibrosis
Lungs
- Increased lung perfusion and gas exchange
- Relaxes bronchi
- Reduced fibrosis
- Reduced degranulation mast cells
- Reduced inflammatory leukocytes
Implicated in
Prostate cancer
Disease
Prostate cancer is the most common form of carcinoma
in men (Lippman et al., 2009). If left untreated, this
form of cancer becomes highly metastatic, primarily to
the bones and lymphatic system. RLN2 is implicated in
the progression, development, and spread of prostate
cancer. RLN2 increases extra-cellular matrix turnover,
promotes tumor invasiveness, and neo-vascularization
(Silvertown et al., 2006).
Liver
- Reduced fibosis
Kidney
- Increased GFR
- Increased ERPF
- Increased Na+ excretion
- Reduced fibrosis
Ovary
- Follicular ripening
- Germ cell maturation
Uterus
- Angiogenesis
- Endometrial thickening
Cervix
- Softening (shift from collagenous to more elastic
tissue)
Pelvic ligaments
- Softening (shift from collagenous to more elastic
tissue)
Mammary gland
- Differentiation and development
Prostate
- Increased sperm motility
- Possible role in hypertrophy and neoplastic change
Testis
- Possible role in testicular descent in rats
Cancer
- Angiogenesis
- Vasodilation
- Reduced fibrosis
- Reduced apoptosis
Prognosis
Given that circulating relaxin increases in experimental
models of prostate cancer, it is possible RLN2 may be
employed as an early marker for prostate cancer and act
as a screening mechanism in clinical settings.
Furthermore, RLN2 exhibits the potential for genetic
therapy to target and neutralize this gene as a novel
treatment for prostate cancer.
Oncogenesis
RLN2 has been implicated in the progression of
prostate tumors. RLN2 expression is increased in
prostate tumors (Silvertown et al., 2006). Antagonism
with analogues of RLN2 (Silvertown et al., 2007)
demonstrates antagonistic properties and impairs
prostate tumor growth and development.
Breast cancer
Disease
Breast cancer is the most common form of carcinoma
in women. RLN2 increases the invasiveness of breast
cancer cells via the induction of matrix
metalloproteinases (MMPs) (Binder et al., 2002).
Circulating relaxin also increases in patients with breast
cancer (Binder et al., 2004).
Prognosis
Since serum relaxin concentrations are increased in
patients with breast cancer, relaxin may be used as a
screening tool for breast cancer. Furthermore, RLN2
may be targeted for genetic therapy as a novel
treatment for breast cancer.
Oncogenesis
RLN2 increases the oncogenic potential of breast
cancer cells by stimulating growth, invasiveness, and
metastasis.
Homology
Generally 30-60% sequence homology is observed
between relaxin 2 among species.
Mutations
Thyroid cancer
Disease
There are four types of thyroid cancer: papillary,
folliculary, medullary, and anaplastic. While limited
research has been conducted with regards to RLN2 and
thyroid cancer, it is possible relaxin enhances the
course and development of thyroid cancer.
Note
It is assumed that the members of the relaxin-gene
family are predominantly functional mutations of an
original relaxin gene (RLN3) located on chromosome
19 at 19p13.3 and translocated at some stage
predominantly to chromosome 9.
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(9)
843
RLN2 (relaxin 2)
Willcox JM, Summerlee AJS
Binder C, Hagemann T, Husen B, Schulz M, Einspanier A.
Relaxin enhances in-vitro invasiveness of breast cancer cell
lines by up-regulation of matrix metalloproteases. Mol Hum
Reprod. 2002 Sep;8(9):789-96
Oncogenesis
RLN2 acts as an autocrine/paracrine factor to enhance
growth and invasiveness of thyroid cancer cells
(Hombach-Klonisch et al., 2006). RLN2 may also
increase motility of thyroid cancer cells thereby
contributing to increased metastatic potential.
Silvertown JD, Geddes BJ, Summerlee AJ. Adenovirusmediated expression of human prorelaxin promotes the
invasive potential of canine mammary cancer cells.
Endocrinology. 2003 Aug;144(8):3683-91
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